Aprotic nucleophilic solvents

Another general method for converting alcohols to halides involves reactions with halides of certain nonmetallic elements. Thionyl chloride, phosphorus trichloride, and phosphorus tribromide are the most common examples of this group of reagents. These reagents are suitable for alcohols that are neither acid sensitive nor prone to structural rearrangement. The reaction of alcohols with thionyl chloride initially results in the formation of a chlorosulfite ester. There are two mechanisms by which the chlorosulfite can be converted to a chloride. In aprotic nucleophilic solvents, such as dioxane, solvent participation can lead to overall retention of configuration.7... 

Most thiirene dioxides (and oxides) have been prepared through a modified Ramberg-Backlund reaction as the last crucial cyclization step, as illustrated in equation 40 for the benzylic series . Synthesis of thiirene dioxides requires two major modifications of the originally employed reaction first, the inorganic base has to be replaced by the less basic and less nucleophilic triethylamine - and second, the aqueous media has to be substituted by an aprotic organic solvent (e.g. methylene chloride). Under these mild reaction conditions the isolation of aryl-substituted thiirene dioxides (and oxides) is feasible . In fact, this is the most convenient way for the preparation of the aryl-disubstituted three-membered ring sulfones and sulfoxides. ... 

For carbon-carbon bond-formation purposes, S 2 nucleophilic substitutions are frequently used. Simple S 2 nucleophilic substitution reactions are generally slower in aqueous conditions than in aprotic organic solvents. This has been attributed to the solvation of nucleophiles in water. As previously mentioned in Section 5.2, Breslow and co-workers have found that cosolvents such as ethanol increase the solubility of hydrophobic molecules in water and provide interesting results for nucleophilic substitutions (Scheme 6.1). In alkylations of phenoxide ions by benzylic chlorides, S/y2 substitutions can occur both at the phenoxide oxygen and at the ortho and para positions of the ring. In fact, carbon alkylation occurs in water but not in nonpolar organic solvents and it is observed only when the phenoxide has at least one methyl substituent ortho, meta, or para). The effects of phenol substituents and of cosolvents on the rates of the competing alkylation processes... 

The polymers used in this study were prepared by a nucleophilic activated aromatic substitution reaction of a bisphenate and dihalo diphenyl sulfone ( ). The reaction was carried out in an aprotic dipolar solvent (NMP) at 170°C in the presence of potassium carbonate (Scheme 1) (5,6). The polymers were purified by repeated precipitation into methanol/water, followed by drying to constant weight. The bisphenols used were bisphenol-A (Bis-A), hydroquinone (Hq) and biphenol (Bp). Thus, the aliphatic character of Bis-A could be removed while retaining a similar aromatic content and structure. The use of biphenol allows an investigation of the possible effect of extended conjugation on the radiation degradation. 

These results were assumed to be ascribed to the neighboring group participation via the intermediary cyclic carbocation (4,) as shown in equation 4, as well as the high nucleophilicity of DTC and acceleration by use of the dipolar aprotic (DA) solvent. The formation and reactivity (stability) of such carbocation were examined at length with the corresponding... 

Aromatic nucleophilic radiofluorinations are usually performed in aprotic polar solvents, such as dimethyl sulfoxide (DMSO), sulfolane or dimethylacetamide, and often under basic conditions (because of the presence of Kryptofix-222 / potassium carbonate). Completion of the p F]fluoride incorporation often requires moderate to high temperatures (100-170 °C) for 10-30 min. Microwave technology can be a successful application here, resulting in improved yields and shorter reaction times [29,170-173],... 

Dihydropyrroles have recently become readily available by ring-closing metathesis. For this purpose, N-acylated or N-sulfonylated bis(allyl)amines are treated with catalytic amounts of a ruthenium carbene complex, whereupon cyclization to the dihydropyrrole occurs (Entries 6 and 7, Table 15.3 [30,31]). Catalysis by carbene complexes is most efficient in aprotic, non-nucleophilic solvents, and can also be conducted on hydrophobic supports such as cross-linked polystyrene. Free amines or other soft nucleophiles might, however, compete with the alkene for electrophilic attack by the catalyst, and should therefore be avoided. 

In contrast, alkylaryl ethers can be produced in analogy to the Dow process (Figure 5.62, top). Alkali metal alkoxides are even more basic/nucleophilic than alkali metal hydroxides. If, moreover, potassium alkoxide and bromo- or chlorobenzene are reacted in DMSO—i.e. in an aprotic dipolar solvent that does not provide the alkoxide ions with any noticeable stabilization through solvation—very good yields may already be achieved at room temperature (Figure 5.62, bottom). 

Sn2 (with good nucleophiles solvent can be protic or, better, aprotic) or SNI (with poor nucleophiles and polar solvents)... 

The reactions of terminal perfluoroolefins with oA/zo-bifunctional benzenes used as nucleophilic reagents result in the five-, seven-, and nine-membered benzoheterocycles. In this case, aprotic dipolar solvents are generally employed, and the base is triethylamine. Thus the products of the reactions of oA/zosubstituted anilines with terminal perfluoroolefins are five-membered benzoheterocyclic compounds. 

On the other hand, the ionization of chloro-triphenylmethane is also favored by EPD solvents. Since the developing carbenium ion is an electrophilic species, it readily interacts with nucleophilic solvents. Thus, the extent of ionization of chlorotriphenylmethane in nitrobenzene increases on the addition of aprotic EPD solvents in direct relation to the donor number [158], See reference [299] for a study of ionization and dissociation equilibria of other halo-triphenylmethanes in solution (PhsC—X with X = F, Cl, Br). 

The presentation of the rearranging intermediates as mesoionic ground-state species (102 and 106) has gained wide acceptance as a tool for interpretation and prediction of structural changes in this field. The intervention of such intermediates is suggested by the facile incorporation of nucleophilic solvent molecules in the course of the photochemical transformation of dienones, and by a number of acid-catalyzed non-photolytic reactions which either parallel the phototsomerizations or correlate photoproducts from reactions in protic and aprotic media. 

Sodium borohydride, a representative borohydride reagent, behaves as an effective source of nucleophilic hydride in an aprotic polar solvent, such as DMSO, sulfolane, HMPA, DMF or diglyme, and is used for the reduction of alkyl halides. As shown in Table 3, primary and secondary iodides, bromides and chlorides are converted to hydrocarbons at temperatures between 25 and 100 C using sodium borohydride. Vicinal dihalides, such as 1,2-dibromooctane, are smoothly converted to the corresponding saturated hydrocarbons, in contrast to the reductions using LiAlH4 or low-valent metal salts, which predominantly afford alkenes. 

A carbocationic intermediate is formed in both the SnI and the El mechanisms. After the carbocation is formed, addition of a nucleophile leads to an overall substitution reaction, whereas fragmentation leads to an overall elimination reaction, so there is a competition between the two modes of reaction. It is possible to predict whether substitution or elimination dominates, just as it is possible to predict whether Sn2 or E2 will predominate under basic conditions. Predicting which pathway dominates is easier under acidic conditions, though. Addition is favored in hydroxylic (i.e., nucleophilic) solvents (RCO2H, ROH, II2O) and when the nucleophile is contained in the same molecule, whereas fragmentation is favored in aprotic solvents. In other words, substitution occurs when the carbocation intermediate can be rapidly intercepted by a nucleophile, and elimination occurs when it cannot. 

Figure 14.11 Nucleophilic aliphatic substitution of a mesylate ester leaving group using fluoride ion as cesium salt in protic and aprotic organic solvents.

Table 14.5 Yields of example radiopharmaceuticals labeled with [18F]fluoride ion using nucleophilic substitution reactions performed in protic solvent systems compared with literature methods utilizing aprotic organic solvents...

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